6‑OH-Phenanthroquinolizidine Alkaloid and Its Derivatives Exert Potent Anticancer Activity by Delaying S Phase Progression

To discover new phenanthroindolizidine
and phenanthroquinolizidine
alkaloids as potential anticancer drug candidates, non-natural 6-O-desmethylcryptopleurine (2) and its derivatives
were prepared. Most of the new compounds exhibited potent antiproliferative
activity against A549 and BEL-7402 cells, with the lowest IC50 being 3 nM. Optically pure 2-R was further evaluated
against a panel of 30 cancer cell lines and found to inhibit the proliferation
of all tested cell lines, including three multidrug-resistant cell
lines, with an average IC50 value of 2.1 nM, which is much
lower than that of previously reported phenanthroindolizidine DCB-3503
(1, IC50: 166.7 nM). A mechanistic evaluation
showed that 2-R potently inhibited cell growth and colony
formation, which are associated with a delay in S phase progression
through the inhibition of DNA synthesis. These results along with
further study on the safety profile of these compounds will facilitate
the discovery of new phenanthro­indolizidine and phenanthro­quinolizidine
alkaloids for use as anticancer drug candidates.